The real progesterone story: Exploring the Makena drug controversy

Key Points

I have written about preterm birth many times on these editorial pages. After years of reciting a litany of grim statistics, such as the seemingly ever-increasing prevalence of prematurity and our lack of effective treatments, there has been much to celebrate of late. The preterm birth rate in the United States actually has declined for the past several years to 12.3% of live births in 2008 from an all-time high of 12.8% in 2006.¹

While some of this drop can be attributed to a reduction in higher-order multiples and a decrease in elective late-preterm deliveries, the introduction of progesterone therapy also likely has had an impact. Thus, the recent Makena controversy, in which a pharmaceutical company obtained Food and Drug Administration (FDA) "orphan drug" status for 17 α-hydroxyprogesterone (17OHP) for the prevention of preterm birth and proceeded to increase the drug's price many times higher than that charged by compounding pharmacies, engaged, enraged, and energized ob/gyns to a degree unparalleled in our discipline's history.

However, lost in the ensuing tumult was a crucial study that may dramatically alter our approach to prematurity prevention and may someday render moot the 17OHP controversy.

The results of the first 17OHP trial, reported in 1975, compared pregnancy outcomes in 43 at-risk women treated with 250 mg of weekly intramuscular 17OHP versus placebo and found fewer preterm births and a lower perinatal mortality rate following progestin treatment.² Mean gestational age at delivery and birth weight also were greater in the 17OHP group (38.6±1.6 weeks vs 35.2±6.7 weeks; and 2,836±412 vs 2,361 g±1,085 g; P<0.05).

More important, the perinatal mortality rate in the 17OHP group was significantly less than that observed in the placebo group (0% vs 27%; (P<0.05). In 1985, Yemini et al duplicated these findings in a randomized, controlled trial among 80 similarly defined high-risk women.³ However, a negative study in 1983 among relatively low-risk active-duty military personnel prompted a loss of interest in 17OHP.⁴

Then in 2003, 2 studies swiftly restored the agent's "reputation" as a prophylactic treatment for preterm birth. Meis and associates recruited 463 patients with a history of spontaneous preterm birth, randomized them in a 2:1 ratio to 17OHP or placebo from 16 to 20 weeks until 36 weeks, and showed that the progestin significantly reduced the risk of delivery at less than 37 weeks (relative risk [RR], 0.66; 95% Confidence Interval [CI], 0.54-0.81), less than 35 weeks (RR, 0.67; 95% CI, 0.48-0.93), and less than 32 weeks (RR, 0.58; 95% CI, 0.37-0.91).⁵ Infants of 17OHP-treated women also had significantly less necrotizing enterocolitis, intraventricular hemorrhage, and need for oxygen.

In another study, published 3 months earlier, da Fonseca and colleagues administered 100 mg vaginal progesterone or placebo from 24 to 34 weeks to 142 women at increased risk for preterm delivery in a randomized, placebo-controlled, double-blind study and noted that contraction frequency was reduced, delivery at less than 37 weeks occurred less frequently (13.8% vs 28.5%; P=0.03), and delivery at less than 34 weeks was less common (2.7% vs 18.5%; P=0.002) in the progesterone group.⁶ This study also suggested that vaginal progesterone might be comparable to 17OHP.

These studies prompted the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) to opine, "Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous preterm birth due to spontaneous preterm labor or premature rupture of membranes."⁷

However, since that time it has not always been easy for ob/gyns to administer 17OHP because it was not FDA-approved for this indication and it had to be obtained using a patient-specific prescription at a compounding pharmacy. Nevertheless, 17OHP was generally available at a price of approximately $10 to $40 per dose.